Vascular disease is the leading cause of death in the United States. Neural-tube defects are a major contributor to perinatal morbidity and mortality. Elevated levels of plasma homocysteine (a non-protein amino acid) have been found to correlate with an increased risk of NTD and vascular disease. Methionine synthase (MS) catalyzes the vitamin B12 dependent, interconversion of homocysteine and 5-methyltetrahydrofolate to methionine and tetrahydrofolate. This is one of the few homocysteine consuming reactions in the body and reduced MS activity is predicted to lead to increased plasma homocysteine. We have cloned the human MS gene and demonstrated that hyperhomocysteinemia in a subset of patients is in fact due to mutations in the MS gene. The full genomic structure of the MS gene is currently being determined. Once all MS exons have been identified, mutation screening assays will be developed. Patients with elevated homocysteine levels and premature vascular disease will be screened for MS mutations. Similar assays will be performed on families with children affected with NTDs. In addition to the human genetic studies, we will use homologous recombination techniques to create a mouse model of MS deficiency.